Label-free, non-optical detection of intact SARS-CoV-2 virions in native human saliva via microscale surface ion...

The COVID-19 pandemic underscored the need for deployable point-of-care (POC) diagnostics capable of rapid viral detection in complex biofluids. While antigen-based tests offer advantages over reverse transcriptase polymerase chain reaction (RT-PCR) in speed and accessibility, many platforms remain limited by labeling requirements, optical readout, or sample pretreatment. Here, we report the first demonstration of label-free, non-optical, direct detection of intact SARS-CoV-2 virions in native human saliva without sample pretreatment using a microscale surface ion conduction ( μSIC) sensor. This work further represents the first application of a μSIC sensor to clinical samples, validated using saliva from COVID-19 patients. In this approach, virions bind to a packed bed of probe-modified microbeads, producing a concentration-dependent shift in ionic current arising from modulation of surface ion conduction, even under high ionic strength conditions. The μSIC sensor achieves a limit of detection of 8.5 × 10⁶ copies/mL for chemically inactivated virions, within clinically relevant concentration ranges, and delivers results within 1 h. Notably, the active virus in patient-derived saliva produces a significantly larger signal than the inactivated virus, consistent with inactivation-induced changes in antigen binding. The sensor exhibits high selectivity for SARS-CoV-2 in the presence of non-target human coronaviruses. These results demonstrate that specific binding of nanometer-scale virions can measurably alter ionic conductivity along microscale bead surfaces, enabling robust detection in native biofluids. Owing to its simplicity, adaptability, and compatibility with POC implementation, the μSIC platform provides a versatile framework for antigen-based diagnostics targeting emerging infectious diseases.